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Rational and Predictable Chemoselective Synthesis of Oligoamines via Buchwald–Hartwig Amination of (Hetero)Aryl Chlorides Employing Mor-DalPhos

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posted on 20.01.2012, 00:00 by Bennett J. Tardiff, Robert McDonald, Michael J. Ferguson, Mark Stradiotto
We report a diverse demonstration of synthetically useful chemoselectivity in the synthesis of di-, tri-, and tetraamines (62 examples) by use of Buchwald–Hartwig amination employing a single catalyst system ([Pd­(cinnamyl)­Cl]2/L1; L1 = N-(2-(di­(1-adamantyl)­phosphino)­phenyl)­morpholine, Mor-DalPhos). Competition reactions established the following relative preference of this catalyst system for amine coupling partners: linear primary alkylamines and imines > unhindered electron-rich primary anilines, primary hydrazones, N,N-dialkylhydrazines, and cyclic primary alkylamines > unhindered electron-deficient primary anilines, α-branched acyclic primary alkylamines, hindered electron-rich primary anilines ≫ cyclic and acyclic secondary dialkylamines, secondary alkyl/aryl and diarylamines, α,α-branched primary alkylamines, and primary amides. The new isomeric ligand N-(4-(di­(1-adamantyl)­phosphino)­phenyl)­morpholine (p-Mor-DalPhos, L2) was prepared in 63% yield and was crystallographically characterized; the [Pd­(cinnamyl)­Cl]2/L2 catalyst system exhibited divergent reactivity. Application of the reactivity trends established for [Pd­(cinnamyl)­Cl]2/L1 toward the chemoselective synthesis of di-, tri-, and tetraamines was achieved. Preferential arylation was observed at the primary alkylamine position within 2-(4-aminophenyl)­ethylamine with [Pd­(cinnamyl)­Cl]2/L1 and 4-chlorotoluene (affording 5a); the alternative regioisomer (5a′) was obtained when using [Pd­(cinnamyl)­Cl]2/L2. These observations are in keeping with coordination chemistry studies, whereby binding of 2-(4-aminophenyl)­ethylamine to the in situ generated [(L1)­Pd­(p-tolyl)]+ fragment occurred via the primary amine moiety, affording the crystallographically characterized adduct [(L1)­Pd­(p-tolyl)­(NH2CH2CH2(4-C6H4NH2)]+OTf (7) in 72% yield.